Anti-inflammatory agents
Inventors
Hansen, Henrik C. • Wagner, Gregory S. • Attwell, Sarah C. • McLure, Kevin G. • Kulikowski, Ewelina B.
Assignees
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Publication Number
US-9757368-B2
Publication Date
2017-09-12
Expiration Date
Abstract
Disclosed are methods of regulating interleukin-6 (IL-6) and/or vascular cell adhesion molecule-1 (VCAM-1) and methods of treating and/or preventing cardiovascular and inflammatory diseases and related disease states, such as, for example, atherosclerosis, asthma, arthritis, cancer, multiple sclerosis, psoriasis, and inflammatory bowel diseases, and autoimmune disease(s) by administering a naturally occurring or synthetic quinazolone derivative. The invention provides novel synthetic quinazolone compounds, as well as pharmaceutical compositions comprising those compounds.
Core Innovation
The invention relates to quinazolone derivatives, including compounds of Formula I and Formula II, together with stereoisomers, tautomers, pharmaceutically acceptable salts, hydrates, prodrugs, and solvates. The disclosed chemical scope includes constrained substitution-variable embodiments, extensive substituent definitions, and enumerated compound embodiments, including quinazolin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives with phenoxyacetic acid/amide structural motifs.
A key part of the invention is the regulation of interleukin-6 (IL-6) and/or vascular cell adhesion molecule-1 (VCAM-1). The description connects IL-6 and VCAM-1 to leukocyte recruitment and inflammatory progression, particularly in atherosclerosis and other inflammatory conditions, and states that the compounds inhibit IL-6 and/or VCAM-1 expression.
The invention further provides methods of treating and/or preventing diseases associated with IL-6 and/or VCAM-1 by administering therapeutically effective amounts of Formula I and Formula II compounds. The disease areas described include cardiovascular and non-cardiovascular inflammatory disorders, inflammatory disease, cardiovascular disease, atherosclerosis, asthma, arthritis, cancer, multiple sclerosis, psoriasis, inflammatory bowel disease, autoimmune disorders, and cancer associated with elevated IL-6.
Claims Coverage
The consolidated claim coverage includes independent claims directed to treatment or reduction of risk for IL-6-mediated inflammatory disease, asthma, chronic obstructive pulmonary disease (COPD), non-cardiovascular inflammatory disease, and cancer associated with elevated IL-6. The inventive features center on administering therapeutically effective amounts of compositions containing Formula II compounds or enumerated compounds, with defined structural variables, stated provisos, and in one claim an explicit exclusion of a specific quinazolin-4(3H)-one compound.
Treating or reducing the risk of IL-6-mediated inflammatory disease with Formula II composition
Administering a therapeutically effective amount of a composition consisting essentially of a compound of Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, with P, V, W, U, Ra1/Ra2/Ra3/Ra4, Rb2/Rb3/Rb5/Rb6, R5, and XRd defined by specified option sets and exclusions.
Treating or reducing the risk of non-cardiovascular IL-6-mediated inflammatory disease using selected compounds
Administering a therapeutically effective amount of a composition consisting essentially of a compound selected from an enumerated list of specific quinazolinone/pyrido[2,3-d]pyrimidinone and related compounds, including tautomers, stereoisomers, pharmaceutically acceptable salts, and hydrates thereof.
Treating cancer associated with elevated IL-6 with Formula II
Administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, with defined substituent variables and stated structural exclusions.
Treating IL-6-mediated inflammatory disease with a specific compound exclusion
Administering a therapeutically effective amount of at least one compound of Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein the compound is not 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one.
Across the independent claims, the coverage is directed to administering Formula II compounds or enumerated compounds for IL-6-mediated inflammatory disease, asthma, COPD, non-cardiovascular inflammatory disease, and cancer associated with elevated IL-6. The claims are defined by extensive structural limitations, allowance for stereoisomers, tautomers, salts, and hydrates, and, in one claim, an explicit compound exclusion.
Stated Advantages
Regulates interleukin-6 (IL-6) and/or vascular cell adhesion molecule-1 (VCAM-1).
Inhibits IL-6 and/or VCAM-1 expression.
Treats and/or prevents cardiovascular and inflammatory diseases.
Reduces risk of acquiring IL-6-mediated inflammatory disease.
Treats cancer associated with elevated levels of IL-6.
Documented Applications
Treating or reducing the risk of acquiring asthma.
Treating or reducing the risk of acquiring chronic obstructive pulmonary disease (COPD).
Treating or reducing the risk of acquiring a non-cardiovascular inflammatory disease mediated by IL-6.
Treating cancer associated with elevated levels of IL-6.
Treating atherosclerosis.
Treating inflammatory diseases including asthma, arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, and autoimmune disorders.
Cystic fibrosis; post-transplantation late and chronic solid organ rejection; systemic lupus erythematosus; ocular inflammation; uveitis; rhinitis; glomerulonephritis; Grave's disease; gastrointestinal allergies; conjunctivitis.
Multiple myeloma; lymphoma; leukemia; solid tumors; prostate and bladder cancers; cardiac myxoma; tumor-induced cachexia; cancer-associated depression; cerebral edema secondary to brain tumors; hormone-independent prostate cancer; B cell lymphoma; AIDS-associated lymphoma; metastatic renal cell carcinoma.
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